First trimester PAPP‐A in the detection of non‐Down syndrome aneuploidy
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Abstract Combined first trimester screening using pregnancy associated plasma protein‐A (PAPP‐A), free β‐human chorionic gonadotrophin, and nuchal translucency (NT), is currently accepted as probably the best combination for the detection of Down syndrome (DS). Current first trimester algorithms provide computed risks only for DS. However, low PAPP‐A is also associated with other chromosome anomalies such as trisomy 13, 18, and sex chromosome aneuploidy. Thus, using currently available algorithms, some chromosome anomalies may not be detected. The purpose of the present study was to establish a low‐end cut‐off value for PAPP‐A that would increase the detection rates for non‐DS chromosome anomalies. The study included 1408 patients who underwent combined first trimester screening. To determine a low‐end cut‐off value for PAPP‐A, a Receiver–Operator Characteristic (ROC) curve analysis was performed. In the entire study group there were 18 cases of chromosome anomalies (trisomy 21, 13, 18, sex chromosome anomalies), 14 of which were among screen‐positive patients, a detection rate of 77.7% for all chromosome anomalies (95% CI: 55.7–99.7%). ROC curve analysis detected a statistically significant cut‐off for PAPP‐A at 0.25 MoM. If the definition of screen‐positive were to also include patients with PAPP‐A<0.25 MoM, the detection rate would increase to 88.8% for all chromosome anomalies (95% CI: 71.6–106%). This low cut‐off value may be used until specific algorithms are implemented for non‐Down syndrome aneuploidy. Copyright © 2001 John Wiley & Sons, Ltd.Keywords:
Trisomy
False positive rate
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Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer's disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or 'dose' of APP is thought to be the cause of this early-onset Alzheimer's disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer's disease in people who have Down syndrome.
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Mice polytransgenic for chromosome 21 genes DSCR3, 5, 6, 9, and TTC3 within the Down Syndrome Critical Region-1 represent an animal model for Down Syndrome (DS). In a proteomic approach, we show a series of altered hippocampal protein levels that may be caused by overexpression of at least one of the five chromosome 21 genes and that fit fear-conditioned memory defects and were observed to be dysregulated in human fetal DS.
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Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk for Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.
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Down syndrome (DS) is caused by an extra copy of the long arm of human chromosome 21 (HSA21) and the increased expression, due to dosage, of HSA21 encoded genes. In addition to intellectual disability, all individuals with DS develop the neuropathology of Alzheimer's Disease (AD) by age 30-40. The amyloid precursor protein gene, APP, that is mutated or duplicated in some familial AD (FAD), is encoded by HSA21, over expressed in DS, and a candidate for causing AD in DS. However, only half of those with DS will develop the AD-like dementia by age 50-60, suggesting that additional HSA21 genes may modulate the effects of APP triplication, and/or protect the DS brain from early onset progression to dementia in spite of neuropathology. In sporadic AD and mouse models of FAD, abnormal levels of a diverse set of proteins, including receptors, scaffold proteins, kinases, phosphatases and cytokines, have been documented, but nothing is known about their possible roles in AD in DS. Here, we compare expression of 26 AD-related proteins in hippocampus of four mouse models of DS, the Ts65Dn, Tc1, Dp (10)1Yey and Dp (17)1Yey, that together provided trisomy of partially overlapping subsets of all HSA21 genes or mouse orthologs. In the Dp(10)1Yey, that is trisomic for HSA21 orthologs mapping to mouse chromosome 10, twelve of 26 AD-related proteins were elevated, while in the Tc1, Dp(17)1Yey and the popular Ts65Dn, six, four and two differed from littermate controls. These data suggest that genes mapping to the HSA21 orthologous regions of mouse chromosomes 10 and 17 contribute to protein perturbations in the DS brain, and possibly AD in DS. Considering the different phenotypic features of the four DS mouse models further suggests that some protein abnormalities may be compensatory and protective for brain function and/or that learning and memory deficits may be age-dependent.
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Abstract Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP , influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP , likely modulate Alzheimer’s disease in people who have Down syndrome.
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Abstract: Down syndrome (DS), also known as trisomy 21, is the most common genetic cause of intellectual disability (ID). Although ID can be mild, the average intelligence quotient is in the range of 40–50. All individuals with DS will also develop the neuropathology of Alzheimer’s disease (AD) by the age of 30–40 years, and approximately half will display an AD-like dementia by the age of 60 years. DS is caused by an extra copy of the long arm of human chromosome 21 (Hsa21) and the consequent elevated levels of expression, due to dosage, of trisomic genes. Despite a worldwide incidence of one in 700–1,000 live births, there are currently no pharmacological treatments available for ID or AD in DS. However, over the last several years, very promising results have been obtained with a mouse model of DS, the Ts65Dn. A diverse array of drugs has been shown to rescue, or partially rescue, DS-relevant deficits in learning and memory and abnormalities in cellular and electrophysiological features seen in the Ts65Dn. These results suggest that some level of amelioration or prevention of cognitive deficits in people with DS may be possible. Here, we review information from the preclinical evaluations in the Ts65Dn, how drugs were selected, how efficacy was judged, and how outcomes differ, or not, among studies. We also summarize the current state of human clinical trials for ID and AD in DS. Lastly, we describe the genetic limitations of the Ts65Dn as a model of DS, and in the preclinical testing of pharmacotherapeutics, and suggest additional targets to be considered for potential pharmacotherapies. Keywords: Ts65Dn, pharmacotherapy, clinical trials, Hsa21
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Abstract Combined first trimester screening using pregnancy associated plasma protein‐A (PAPP‐A), free β‐human chorionic gonadotrophin, and nuchal translucency (NT), is currently accepted as probably the best combination for the detection of Down syndrome (DS). Current first trimester algorithms provide computed risks only for DS. However, low PAPP‐A is also associated with other chromosome anomalies such as trisomy 13, 18, and sex chromosome aneuploidy. Thus, using currently available algorithms, some chromosome anomalies may not be detected. The purpose of the present study was to establish a low‐end cut‐off value for PAPP‐A that would increase the detection rates for non‐DS chromosome anomalies. The study included 1408 patients who underwent combined first trimester screening. To determine a low‐end cut‐off value for PAPP‐A, a Receiver–Operator Characteristic (ROC) curve analysis was performed. In the entire study group there were 18 cases of chromosome anomalies (trisomy 21, 13, 18, sex chromosome anomalies), 14 of which were among screen‐positive patients, a detection rate of 77.7% for all chromosome anomalies (95% CI: 55.7–99.7%). ROC curve analysis detected a statistically significant cut‐off for PAPP‐A at 0.25 MoM. If the definition of screen‐positive were to also include patients with PAPP‐A<0.25 MoM, the detection rate would increase to 88.8% for all chromosome anomalies (95% CI: 71.6–106%). This low cut‐off value may be used until specific algorithms are implemented for non‐Down syndrome aneuploidy. Copyright © 2001 John Wiley & Sons, Ltd.
Trisomy
False positive rate
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Citations (17)